This invention relates to novel compounds, pharmaceutical compositions thereof, and their use as anti-inflammatory agents and for the treatment of cell proliferation and cancer in mammals.
Over the past three decades, it has been firmly established that the in vivo modulation of levels of the polyunsaturated fatty acid, arachidonic acid (AA) and oxygenated metabolites of arachidonic acid is intimately linked to human disease. Our laboratories have focused on the pathways and enzyme activities that acylate AA into membrane phospholipid of inflammatory and neoplastic cells (for a review, see Chilton et al., Biochim. Biophys. Acta 1299: 1-15 (1996)). These studies indicate that there are as many as 20 different arachidonate-containing phospholipid molecular species in any given inflammatory or neoplastic cell type. We have demonstrated that AA moves through different AA-containing phospholipid molecular species in a sequential fashion requiring several different enzyme activities (FIG. 1). Initially AA is converted to AA-CoA by fatty acyl CoA synthase(s). There appears to be specific fatty acyl CoA synthase(s) which utilize AA but not other fatty acids. Once formed, arachidonoyl-CoA may be incorporated into 1-acyl-2-lyso-sn-glycero-3-phosphocholine by CoA-dependent acyl transferase(s). This AA in 1-acyl-2-AA-sn-glycero-3-phosphocholine is then transferred to 1-ether-linked phospholipids such as 1-alkyl-2-AA-sn-glycero-3-phosphocholine and 1-alk-1-enyl-2-AA-sn-glycero-phosphoethanolamine. 1-Ether-linked phospholipids contain the bulk of AA found in most inflammatory and neoplastic cells. This latter reaction is orchestrated by the action of the enzyme CoA-independent transacylase (CoA-IT).
Coenzyme A-independent transacylase (CoA-IT) is an enzyme responsible for the movement of arachidonate between phospholipid molecular species of inflammatory cells. CoA-IT removes arachidonate from the sn-2 position of 1-acyl-containing phospholipids, such as 1-acyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-acyl-2-arachidonoyl-GPC). It then transfers that arachidonate to a suitable lyso-phospholipid acceptor, such as 1-alkyl-2-lyso-GPC and 1-alkenyl-2-lyso-sn-glycero-3-phosphoethanolamine (Sugiura et al., J. Biol. Chem. 262: 1199-1205 (1987); Kramer and Deykin, Biol. Chem. 258: 13806-13811 (1983); Chilton et al., J. Biol. Chem. 258: 7268-7271 (1983)). This activity is selective for 20 carbon fatty acyl groups and is the mechanism by which inflammatory cells move arachidonate into specific phospholipid pools prior to its release (Winkler and Chilton, Drug News Perspec. 6: 133-138 (1993); Snyder et al., J. Lipid Mediat. 10: 25-31 (1994)).
Although the pathway for the incorporation and remodeling of AA among phospholipids have been worked out within inflammatory cells and neoplastic cells, we have only recently begun to understand the functional significance of this pathway. We have recently discovered structurally distinct families of molecules (characterized by SKandF 45905 (2-[2-[3-(4-Chloro-3-trifluoromethylphneyl)ureido]-4-tifluromethylphenoxy]-4,5-dichlorobenzene sulfonic acid) and SKandF 98625 (Diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1yl)heptane phosphonate)) which are capable of inhibiting CoA-IT (Chilton et al., Biochemistry 34: 5403-5410 (1995); Winkler et al., J. Pharmacol. Exp. Ther. 274: 1338-1347 (1995)). When provided acutely or chronically to inflammatory or neoplastic cells, these inhibitors attenuate the movement labeled AA from 1-acyl-linked phospholipids to 1-alkyl- and 1-alkenyl-linked phospholipids (Chilton et al., Biochemistry 34: 5403-5410 (1995)). In addition to SKandF 45905 and SKandF 98625, it has been established that the antineoplastic agent1-0-octadecyl-2-0-methyl-phosphocholine (ET-18-0-CH3) is also a potent inhibitor of the enzyme CoA-IT (Winkler et al., J. Pharmacol. Exp. Ther. 279: 956-966 (1996)). Moreover, other studies revealed that the CoA-IT inhibitors SKandF 45905 and SKandF 98625 possess antiproliferative properties (Surette et al., Biochemistry 35: 9187-9196 (1996); Winkler et al., J. Pharmacol. Exp. Ther. 279: 956-966 (1996)). More specifically, all CoA-IT inhibitors, including ET-18-0-CH3, attenuate cell proliferation and induce apoptosis in several neoplastic cell lines. Structurally related compounds which possess no inhibitory activity toward CoA-IT do not induce apoptosis. In addition, inhibitors of phospholipase A2, 5-lipoxygenase, and cyclooxygenase do not induce apoptosis suggesting that free AA or its metabolites are not responsible for this process. The aforementioned discoveries indicate that blockage of the enzyme CoA-IT is a novel chemotherapeutic approach for the treatment of proliferative disorders such as cancer.
There exists a need to find other CoA-IT inhibitors with better in vivo pharmacological and toxicological profiles. These compounds should block cell proliferation of diseased cells and hence provide potential treatment for cancers, such as leukemia and other proliferative diseases and conditions such as psoriasis.
The present invention is a method to decreasing, inhibiting or reducing disease or disorders of cell proliferation in a mammal, and inducing apoptosis in a mammal, preferably in a human, by inhibition of the enzyme CoA-IT. Therefore the present invention is to the use of an effective amount of a CoA-IT inhibitor of Formula (I) for the treatment of said cell proliferation, in mammals, preferably humans, in need of such treatment, by administering to said human an effective amount of a CoA-IT inhibitory compound, or pharmaceutically acceptable salt thereof. A preferred disease state, for treatment associated with cell proliferation, is psoriasis, rheumatoid arthritis or atherosclerosis.
Another aspect of the present invention is to a method of treating a cancerous cell growth in a mammal, preferably a human, in need of such treatment, which method comprises administering to said mammal an effective amount of a compound of Formula (I). A preferred disease state for treatment associated with cancerous cell growth is leukemia.
Another aspect of the present invention is to a method of inducing apoptosis in a mammal, in need of such treatment which method comprises administering to said human or mammal an effective amount of a CoA-independent transacylase (CoA-IT) inhibitor, of Formula (I).